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Search Results: 1 - 10 of 300819 matches for " Nicholas J. Croucher "
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A High-Resolution View of Genome-Wide Pneumococcal Transformation
Nicholas J. Croucher ,Simon R. Harris,Lars Barquist,Julian Parkhill,Stephen D. Bentley
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002745
Abstract: Transformation is an important mechanism of microbial evolution through which bacteria have been observed to rapidly adapt in response to clinical interventions; examples include facilitating vaccine evasion and the development of penicillin resistance in the major respiratory pathogen Streptococcus pneumoniae. To characterise the process in detail, the genomes of 124 S. pneumoniae isolates produced through in vitro transformation were sequenced and recombination events detected. Those recombinations importing the selected marker were independent of unselected events elsewhere in the genome, the positions of which were not significantly affected by local sequence similarity between donor and recipient or mismatch repair processes. However, both types of recombinations were sometimes mosaic, with multiple non-contiguous segments originating from the same molecule of donor DNA. The lengths of the unselected events were exponentially distributed with a mean of 2.3 kb, implying that recombinations are stochastically resolved with a fixed per base probability of 4.4×10?4 bp?1. This distribution of recombination sizes, coupled with an observed under representation of large insertions within transferred sequence, suggests transformation has the potential to reduce the size of bacterial genomes, and is unlikely to act as an efficient mechanism for the uptake of accessory genomic loci.
Identification, variation and transcription of pneumococcal repeat sequences
Nicholas J Croucher, Georgios S Vernikos, Julian Parkhill, Stephen D Bentley
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-120
Abstract: Analysis of the genome of S. pneumoniae ATCC 700669 revealed the presence of a third repeat family, which we have named SPRITE. All three repeats are present at a reduced density in the genome of the closely related species S. mitis. However, they are almost entirely absent from all other streptococci, although a set of elements related to the pneumococcal BOX repeat was identified in the zoonotic pathogen S. suis. In conjunction with information regarding their distribution within the pneumococcal chromosome, this suggests that it is unlikely that these repeats are specialised sequences performing a particular role for the host, but rather that they constitute parasitic elements. However, comparing insertion sites between pneumococcal sequences indicates that they appear to transpose at a much lower rate than IS elements. Some large BOX elements in S. pneumoniae were found to encode open reading frames on both strands of the genome, whilst another was found to form a composite RNA structure with two T box riboswitches. In multiple cases, such BOX elements were demonstrated as being expressed using directional RNA-seq and RT-PCR.BOX, RUP and SPRITE repeats appear to have proliferated extensively throughout the pneumococcal chromosome during the species' past, but novel insertions are currently occurring at a relatively slow rate. Through their extensive secondary structures, they seem likely to affect the expression of genes with which they are co-transcribed. Software for annotation of these repeats is freely available from ftp://ftp.sanger.ac.uk/pub/pathogens/strep_repeats/ webcite.Small interspersed repeats, spatially separated genomic regions of similar sequence typically < 200 bp in length, are frequently found in bacterial chromosomes [1]. These can be classified as either 'simple', when consisting of a single repeated unit, or 'composite', when comprised of a combination of different subsequences arranged in particular patterns [2]. For example, a number of e
Heterogeneity in the Frequency and Characteristics of Homologous Recombination in Pneumococcal Evolution
Rafal Mostowy equal contributor,Nicholas J. Croucher equal contributor,William P. Hanage,Simon R. Harris,Stephen Bentley,Christophe Fraser
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004300
Abstract: The bacterium Streptococcus pneumoniae (pneumococcus) is one of the most important human bacterial pathogens, and a leading cause of morbidity and mortality worldwide. The pneumococcus is also known for undergoing extensive homologous recombination via transformation with exogenous DNA. It has been shown that recombination has a major impact on the evolution of the pathogen, including acquisition of antibiotic resistance and serotype-switching. Nevertheless, the mechanism and the rates of recombination in an epidemiological context remain poorly understood. Here, we proposed several mathematical models to describe the rate and size of recombination in the evolutionary history of two very distinct pneumococcal lineages, PMEN1 and CC180. We found that, in both lineages, the process of homologous recombination was best described by a heterogeneous model of recombination with single, short, frequent replacements, which we call micro-recombinations, and rarer, multi-fragment, saltational replacements, which we call macro-recombinations. Macro-recombination was associated with major phenotypic changes, including serotype-switching events, and thus was a major driver of the diversification of the pathogen. We critically evaluate biological and epidemiological processes that could give rise to the micro-recombination and macro-recombination processes.
A Strand-Specific RNA–Seq Analysis of the Transcriptome of the Typhoid Bacillus Salmonella Typhi
Timothy T. Perkins,Robert A. Kingsley,Maria C. Fookes,Paul P. Gardner,Keith D. James,Lu Yu,Samuel A. Assefa,Miao He,Nicholas J. Croucher,Derek J. Pickard,Duncan J. Maskell,Julian Parkhill,Jyoti Choudhary,Nicholas R. Thomson,Gordon Dougan
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000569
Abstract: High-density, strand-specific cDNA sequencing (ssRNA–seq) was used to analyze the transcriptome of Salmonella enterica serovar Typhi (S. Typhi). By mapping sequence data to the entire S. Typhi genome, we analyzed the transcriptome in a strand-specific manner and further defined transcribed regions encoded within prophages, pseudogenes, previously un-annotated, and 3′- or 5′-untranslated regions (UTR). An additional 40 novel candidate non-coding RNAs were identified beyond those previously annotated. Proteomic analysis was combined with transcriptome data to confirm and refine the annotation of a number of hpothetical genes. ssRNA–seq was also combined with microarray and proteome analysis to further define the S. Typhi OmpR regulon and identify novel OmpR regulated transcripts. Thus, ssRNA–seq provides a novel and powerful approach to the characterization of the bacterial transcriptome.
Sequence-Based Analysis Uncovers an Abundance of Non-Coding RNA in the Total Transcriptome of Mycobacterium tuberculosis
Kristine B. Arnvig ,I?aki Comas,Nicholas R. Thomson,Joanna Houghton,Helena I. Boshoff,Nicholas J. Croucher,Graham Rose,Timothy T. Perkins,Julian Parkhill,Gordon Dougan,Douglas B. Young
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002342
Abstract: RNA sequencing provides a new perspective on the genome of Mycobacterium tuberculosis by revealing an extensive presence of non-coding RNA, including long 5’ and 3’ untranslated regions, antisense transcripts, and intergenic small RNA (sRNA) molecules. More than a quarter of all sequence reads mapping outside of ribosomal RNA genes represent non-coding RNA, and the density of reads mapping to intergenic regions was more than two-fold higher than that mapping to annotated coding sequences. Selected sRNAs were found at increased abundance in stationary phase cultures and accumulated to remarkably high levels in the lungs of chronically infected mice, indicating a potential contribution to pathogenesis. The ability of tubercle bacilli to adapt to changing environments within the host is critical to their ability to cause disease and to persist during drug treatment; it is likely that novel post-transcriptional regulatory networks will play an important role in these adaptive responses.
Comprehensive Identification of Single Nucleotide Polymorphisms Associated with Beta-lactam Resistance within Pneumococcal Mosaic Genes
Claire Chewapreecha,Pekka Marttinen,Nicholas J. Croucher,Susannah J. Salter,Simon R. Harris,Alison E. Mather,William P. Hanage,David Goldblatt,Francois H. Nosten,Claudia Turner,Paul Turner equal contributor,Stephen D. Bentley equal contributor ,Julian Parkhill equal contributor
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004547
Abstract: Traditional genetic association studies are very difficult in bacteria, as the generally limited recombination leads to large linked haplotype blocks, confounding the identification of causative variants. Beta-lactam antibiotic resistance in Streptococcus pneumoniae arises readily as the bacteria can quickly incorporate DNA fragments encompassing variants that make the transformed strains resistant. However, the causative mutations themselves are embedded within larger recombined blocks, and previous studies have only analysed a limited number of isolates, leading to the description of “mosaic genes” as being responsible for resistance. By comparing a large number of genomes of beta-lactam susceptible and non-susceptible strains, the high frequency of recombination should break up these haplotype blocks and allow the use of genetic association approaches to identify individual causative variants. Here, we performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs) and indels that could confer beta-lactam non-susceptibility using 3,085 Thai and 616 USA pneumococcal isolates as independent datasets for the variant discovery. The large sample sizes allowed us to narrow the source of beta-lactam non-susceptibility from long recombinant fragments down to much smaller loci comprised of discrete or linked SNPs. While some loci appear to be universal resistance determinants, contributing equally to non-susceptibility for at least two classes of beta-lactam antibiotics, some play a larger role in resistance to particular antibiotics. All of the identified loci have a highly non-uniform distribution in the populations. They are enriched not only in vaccine-targeted, but also non-vaccine-targeted lineages, which may raise clinical concerns. Identification of single nucleotide polymorphisms underlying resistance will be essential for future use of genome sequencing to predict antibiotic sensitivity in clinical microbiology.
The multidrug-resistant PMEN1 pneumococcus is a paradigm for genetic success
Kelly L Wyres, Lotte M Lambertsen, Nicholas J Croucher, Lesley McGee, Anne von Gottberg, Josefina Li?ares, Michael R Jacobs, Karl G Kristinsson, Bernard W Beall, Keith P Klugman, Julian Parkhill, Regine Hakenbeck, Stephen D Bentley, Angela B Brueggemann
Genome Biology , 2012, DOI: 10.1186/gb-2012-13-11-r103
Abstract: We discovered that one of the earliest known penicillin-nonsusceptible pneumococci, recovered in 1967 from Australia, was the likely ancestor of PMEN1, since approximately 95% of coding sequences identified within its genome were highly similar to those of PMEN1. The regions of the PMEN1 genome that differed from the ancestor contained genes associated with antibiotic resistance, transmission and virulence. We also revealed that PMEN1 was uniquely promiscuous with its DNA, donating penicillin-resistance genes and sometimes many other genes associated with antibiotic resistance, virulence and cell adherence to many genotypically diverse pneumococci. In particular, we describe two strains in which up to 10% of the PMEN1 genome was acquired in multiple fragments, some as long as 32 kb, distributed around the recipient genomes. This type of directional genetic promiscuity from a single clone to numerous unrelated clones has, to our knowledge, never before been described.These findings suggest that PMEN1 is a paradigm of genetic success both through its epidemiology and promiscuity. These findings also challenge the existing views about horizontal gene transfer among pneumococci.Worldwide, over 1.6 million deaths annually are attributed to the bacterial pathogen Streptococcus pneumoniae, the 'pneumococcus' [1]. This bacterium is a leading cause of otitis media, sinusitis, pneumonia and meningitis, and is associated with high mortality rates in the developing world [1,2]. While many pneumococcal diseases can be successfully treated with antibiotics such as penicillin (and other β-lactams), resistance is a major global problem. The primary pneumococcal penicillin resistance determinants are three of the six penicillin-binding protein (pbp) genes, pbp2x, pbp1a and pbp2b. In penicillin-nonsusceptible pneumococci (PNSP) these genes contain mosaic sequence blocks differing from those of penicillin-susceptible pneumococci (PSP) by up to 25% nucleotide divergence [3,4]. It is be
Dominant Role of Nucleotide Substitution in the Diversification of Serotype 3 Pneumococci over Decades and during a Single Infection
Nicholas J. Croucher ,Andrea M. Mitchell,Katherine A. Gould,Donald Inverarity,Lars Barquist,Theresa Feltwell,Maria C. Fookes,Simon R. Harris,Janina Dordel,Susannah J. Salter,Sarah Browall,Helena Zemlickova,Julian Parkhill,Staffan Normark,Birgitta Henriques-Normark,Jason Hinds,Tim J. Mitchell ,Stephen D. Bentley
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003868
Abstract: Streptococcus pneumoniae of serotype 3 possess a mucoid capsule and cause disease associated with high mortality rates relative to other pneumococci. Phylogenetic analysis of a complete reference genome and 81 draft sequences from clonal complex 180, the predominant serotype 3 clone in much of the world, found most sampled isolates belonged to a clade affected by few diversifying recombinations. However, other isolates indicate significant genetic variation has accumulated over the clonal complex's entire history. Two closely related genomes, one from the blood and another from the cerebrospinal fluid, were obtained from a patient with meningitis. The pair differed in their behaviour in a mouse model of disease and in their susceptibility to antimicrobials, with at least some of these changes attributable to a mutation that up-regulated the patAB efflux pump. This indicates clinically important phenotypic variation can accumulate rapidly through small alterations to the genotype.
Structure and dynamics of the pan-genome of Streptococcus pneumoniae and closely related species
Claudio Donati, N Luisa Hiller, Hervé Tettelin, Alessandro Muzzi, Nicholas J Croucher, Samuel V Angiuoli, Marco Oggioni, Julie C Dunning Hotopp, Fen Z Hu, David R Riley, Antonello Covacci, Tim J Mitchell, Stephen D Bentley, Morgens Kilian, Garth D Ehrlich, Rino Rappuoli, E Richard Moxon, Vega Masignani
Genome Biology , 2010, DOI: 10.1186/gb-2010-11-10-r107
Abstract: Despite evidence of extensive recombination, the S. pneumoniae phylogenetic tree revealed six major lineages. With the exception of serotype 1, the tree correlated poorly with capsular serotype, geographical site of isolation and disease outcome. The distribution of dispensable genes - genes present in more than one strain but not in all strains - was consistent with phylogeny, although horizontal gene transfer events attenuated this correlation in the case of ancient lineages. Homologous recombination, involving short stretches of DNA, was the dominant evolutionary process of the core genome of S. pneumoniae. Genetic exchange occurred both within and across the borders of the species, and S. mitis was the main reservoir of genetic diversity of S. pneumoniae. The pan-genome size of S. pneumoniae increased logarithmically with the number of strains and linearly with the number of polymorphic sites of the sampled genomes, suggesting that acquired genes accumulate proportionately to the age of clones. Most genes associated with pathogenicity were shared by all S. pneumoniae strains, but were also present in S. mitis, S. oralis and S. infantis, indicating that these genes are not sufficient to determine virulence.Genetic exchange with related species sharing the same ecological niche is the main mechanism of evolution of S. pneumoniae. The open pan-genome guarantees the species a quick and economical response to diverse environments.Streptococcus pneumoniae is a major causative agent of human diseases, which include chronic otitis media, sinusitis, pneumonia, septicemia, and meningitis. While other pathogenic streptococci can be easily identified both phenotypically and through molecular phylogenetic analysis, S. pneumoniae is very similar to commensal species of the Mitis group, in particular Streptococcus mitis, Streptococcus oralis and Streptococcus infantis [1].Most strains of these species can take up DNA from the environment and recombine sequences into their chro
Correction: Structure and dynamics of the pan-genome of Streptococcus pneumoniae and closely related species
Claudio Donati, N Luisa Hiller, Hervé Tettelin, Alessandro Muzzi, Nicholas J Croucher, Samuel V Angiuoli, Marco Oggioni, Julie Hotopp, Fen Z Hu, David R Riley, Antonello Covacci, Tim J Mitchell, Stephen D Bentley, Mogens Kilian, Garth D Ehrlich, Rino Rappuoli, E Richard Moxon, Vega Masignani
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-10-140
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